Antineoplastic agents. 499. Synthesis of hystatin 2 and related 1H-benzo[de][1,6]-naphthyridinium salts from aaptamine.

Abstract

The marine sponge constituent aaptamine (1) has been converted to the cancer cell growth inhibitor and antibiotic designated hystatin 2 (8a). Herein, we also report results of an initial SAR evaluation of new benzyl derivatives of aaptamine (1). Single benzylation was found to occur at nitrogen N-4 and led to the formation of the 4-benzylaaptamine derivatives 7a-c, whereas double benzylation gave the quaternary 1H-benzo[de][1,6]-naphthyridinium salts 8a-c. The anticancer and antimicrobial properties of these aaptamine derivatives are described. The quaternary ammonium salts 8a (hystatin 2) and 8b exhibited significant inhibitory activity against the murine P388 lymphocytic leukemia and a minipanel of human cancer cell lines. Salts 8a and 8b also had broad spectrum antimicrobial activities and were most potent against Mycobacterium tuberculosis, Neisseria gonorrhoeae, and Micrococcus luteus. Naphthyridinium chloride 8a was selected for further development, and results of an initial cell cycle analysis and a cDNA microarray study showed effects consistent with inhibition of the S-phase of cell growth.

Cite this paper

@article{Pettit2004AntineoplasticA4, title={Antineoplastic agents. 499. Synthesis of hystatin 2 and related 1H-benzo[de][1,6]-naphthyridinium salts from aaptamine.}, author={George R. Pettit and Holger Hoffmann and Delbert L Herald and Peter M. Blumberg and Ernest Hamel and Jean M. Schmidt and Yung Chang and Robin K. Pettit and Nancy E. Lewin and Larry V. Pearce}, journal={Journal of medicinal chemistry}, year={2004}, volume={47 7}, pages={1775-82} }